Islet cells share promoter hypomethylation independently of expression, but exhibit cell-type-specific methylation in enhancers.
Islet cells share promoter hypomethylation independently of expression, but exhibit cell-type-specific methylation in enhancers.
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DOI：
10.1073/pnas.1713736114
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发表时间：
2017-12-19
影响因子：
11.1
通讯作者：
Dor Y
中科院分区：
文献类型：
--
作者：
Neiman D;Moss J;Hecht M;Magenheim J;Piyanzin S;Shapiro AMJ;de Koning EJP;Razin A;Cedar H;Shemer R;Dor Y
我们已经研究了胰腺α-和β-细胞中DNA甲基化的动力学，并对胰岛细胞身份的建立达成了令人惊讶的见解。不同的胰岛细胞类型在细胞类型特异性基因启动子中缺乏甲基化，而胰岛细胞类型之间的DNA甲基化差异集中在增强子区域。这些发现支持了增强子甲基化在确定细胞身份中的基本作用，并对理解糖尿病中胰岛细胞的可塑性具有意义。DNA启动子甲基化是基因表达的重要决定因素。早期的研究表明，胰岛素基因启动子在表达胰岛素的胰腺β细胞中是唯一未甲基化的，这提供了这种范例的经典例子。在这里，我们表明，胰岛细胞表达胰岛素，胰高血糖素，或生长激素抑制素共享缺乏甲基化的胰岛素和胰高血糖素基因的启动子。这是通过在神经生成素3+胚胎内分泌祖细胞的分化过程中胰岛素和胰高血糖素基因启动子的快速去甲基化来实现的，而不管所选择的特定内分泌细胞类型如何。在含有人胰岛素启动子片段的转基因小鼠中观察到类似的甲基化动力学，指向负责的顺式元件。人类α-和β-细胞的全甲基化组比较揭示了研究结果的一般性：在一种细胞类型中有活性而在另一种细胞类型中沉默的基因倾向于共享去甲基化的启动子，而α-和β-细胞之间的甲基化差异集中在增强子中。这些发现表明了所观察到的胰岛细胞类型的可塑性的表观遗传学基础，并对糖尿病中的β细胞重编程和使用循环DNA的甲基化模式诊断β细胞死亡具有意义。
We have studied the dynamics of DNA methylation in pancreatic α- and β-cells and reached surprising insights into the establishment of islet cell identity. Different islet cell types share lack of methylation in cell-type–specific gene promoters, while DNA methylation differences between islet cell types are concentrated in enhancer regions. The findings support the fundamental role of enhancer methylation in determining cell identity, and have implications for the understanding of islet cell plasticity in diabetes. DNA methylation at promoters is an important determinant of gene expression. Earlier studies suggested that the insulin gene promoter is uniquely unmethylated in insulin-expressing pancreatic β-cells, providing a classic example of this paradigm. Here we show that islet cells expressing insulin, glucagon, or somatostatin share a lack of methylation at the promoters of the insulin and glucagon genes. This is achieved by rapid demethylation of the insulin and glucagon gene promoters during differentiation of Neurogenin3+ embryonic endocrine progenitors, regardless of the specific endocrine cell-type chosen. Similar methylation dynamics were observed in transgenic mice containing a human insulin promoter fragment, pointing to the responsible cis element. Whole-methylome comparison of human α- and β-cells revealed generality of the findings: genes active in one cell type and silent in the other tend to share demethylated promoters, while methylation differences between α- and β-cells are concentrated in enhancers. These findings suggest an epigenetic basis for the observed plastic identity of islet cell types, and have implications for β-cell reprogramming in diabetes and diagnosis of β-cell death using methylation patterns of circulating DNA.
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影响因子：
7.7
作者：
Fisher MM;Watkins RA;Blum J;Evans-Molina C;Chalasani N;DiMeglio LA;Mather KJ;Tersey SA;Mirmira RG
通讯作者：
Mirmira RG
影响因子：
23.9
作者：
Borowiak M;Maehr R;Chen S;Chen AE;Tang W;Fox JL;Schreiber SL;Melton DA
通讯作者：
Melton DA
影响因子：
29
作者：
Reimann F;Habib AM;Tolhurst G;Parker HE;Rogers GJ;Gribble FM
通讯作者：
Gribble FM
影响因子：
15.9
作者：
Herold, Kevan C.;Usmani-Brown, Sahar;Palmer, Jerry P.
通讯作者：
Palmer, Jerry P.
影响因子：
16
作者：
Bock, Christoph;Beerman, Isabel;Lien, Wen-Hui;Smith, Zachary D.;Gu, Hongcang;Boyle, Patrick;Gnirke, Andreas;Fuchs, Elaine;Rossi, Derrick J.;Meissner, Alexander
通讯作者：
Meissner, Alexander